Researchers Question Validity of Treatment Resistant Depression

Treatment resistant depression erroneously focuses on patient characteristics and ignores the efficacy of treatment (or lack thereof).


A new editorial in Psychotherapy and Psychosomatics questions the validity of the concept of treatment resistant depression. Led by Giovanni Fava, from the University of Buffalo, the authors chart the history of treatment resistance in depression and reveal its problematic assumptions. They suggest that an informed study of depressive disorders would take in to account clinical judgment, illness behavior, comorbid conditions, living conditions, and previous treatment history.

A patient is called treatment-resistant when they do not respond well to the trial drug. This article contends that the concept is deceptive as it erroneously assumes that the drug is effective, and a patient’s characteristics cause that failure.


Treatment resistance implies that people who are not responding well to a given treatment do so because of their personal attributes, and not because of treatment ineffectiveness or side-effects. Previous research on treatment resistance has been controversial, with some suggesting that antidepressants can themselves cause treatment resistance and that the same might hold true for antipsychotics.

The authors of this article write that historically the definition of treatment resistance has been contested, with some suggesting that it should only be used when the best therapeutic intervention has been applied. But the superiority of a given intervention is not easy to define.

One set of researchers insisted that treatment resistance should only be used for failure in trials using high-doses of tricyclic antidepressants, which was assumed to be superior to others. However, a recent meta-analysis revealed no such superiority. Other challenges to this concept include assessing what response to a treatment means and how to measure its difference from non-response.

Numerous factors are neglected in these trials. For example, many approaches to treatment resistance only focus on response, partial response, and no response to treatment, and completely disregard active clinical deterioration caused by the said treatment. In other words, while they focus on whether a patient is improving or not, they ignore those who are actively worsening because of the treatment. The patients who worsen are often included under the category of ‘insufficient response’ to treatment.

The authors argue that while any good assessment should consider both the benefits and harms of treatment, in reality, iatrogenic harms such as tardive dyskinesia, insulin resistance, and cardiac/metabolic disturbances are often ignored. They state that certain trial results, while common, do not get proper attention. These include:

  1. The resistance that occurs after a drug is discontinued and then re-administered
  2. Loss of clinical effect – depressive symptoms coming back even when patients are taking the antidepressant
  3. Paradoxical effect – the appearance of new symptoms and worsening of baseline condition when patients are taking the antidepressant
  4. Only temporary improvement when the dosage is increased
  5. Improvement in symptoms when the antidepressant is discontinued

Most importantly, many patients who participate in the trials have discontinued an antidepressant, and the withdrawal effects of discontinuation can adversely influence new trials. Antidepressant withdrawal had been traditionally underestimated, but more recent research reveals that it can be severe and long-lasting. Resultantly, dissenting voices in the discipline, especially in reference to antidepressant withdrawal, are often silenced or manipulated.

The authors insist that one of the few trials (ADAPT trial) that did take into account these factors revealed no significant difference between aripiprazole and placebo for treatment-resistant depression. New research has also challenged the validity of relapse prevention trials of antidepressants, suggesting that what appears as deterioration of the patient when they are taken off the trial antidepressant is actually the withdrawal effect.

Stating that underlying these conceptual problems are issues of flawed methodology, Fava and colleagues trace the history of randomized controlled trials. The double-blind placebo-controlled trial, which has its roots in agricultural science and was of great use for acute diseases such as tuberculosis, does not apply to many current conditions. Unlike many earlier diseases, most clinical complaints are currently for chronic and non-specific issues with a history of previous treatment.

Previous treatments have also been related to iatrogenic morbidity, which is defined as “unfavorable modifications in the course, characteristics, and responsiveness of treatment to an illness that may be related to previously administered therapies.” Thus, most large-scale randomized controlled trials ignore these factors and have a broad inclusion criterion that neglects clinical history. The authors suggest smaller trials with more specific inclusion criteria that attends to comorbid conditions and previous treatment are the way forward.

All these issues have two important clinical implications: administration of ineffective drugs such as ketamine for treating treatment-resistance, and the belief that treatment resistance is a function of a patient’s characteristics and not due to problems with the drug (ineffectiveness, side-effects, etc.). Often this results in psychiatrists augmenting and switching the treatment but never questioning the efficacy of the treatment in the first place.

The authors suggest that this results in ‘cascade iatrogenesis’ where the patients keep getting prescribed more and more medications that eventually have severe adverse effects and contribute to the chronicity of illness. Recently, there has been a global movement to address the problems with such polypharmacy and its dangerous consequences.

The authors write that there are newer and effective conceptualizations of what treatment resistance means. One solution is the sequential model of treatment which entails that a:

“Sequence is performed regardless of the outcome of the first component (whether treatment failure occurred or not) as a pre-planned strategy. In unipolar depression, the sequential use of pharmacotherapy and psychotherapy was found to improve long-term outcome.”

Thus, they suggest that maybe treatment resistance should be reserved for cases where sequential treatment (both pharmacology and therapy) has been used.

Additionally, the effectiveness of a treatment is based on several factors which have both positive and negative effects (therapeutic and counter-therapeutic effects): conditions of living, personal characteristics, treatment setting, level of self-management of the condition, illness behavior (patient’s perception, experience, and behavior towards treatment plan), and past experience with treatment. These factors are usually ignored in the study of treatment-resistant depression.

They conclude that the current approach to treatment resistance is a product of the reductionist medical model, which has been repeatedly challenged in the discipline.



Fava, G. A., Cosci, F., Guidi, J., & Rafanelli, C. (2020). The Deceptive Manifestations of Treatment Resistance in Depression: A New Look at the Problem. Psychotherapy and Psychosomatics, Published online first: April 23, 2020. DOI: 10.1159/000507227 (Link)


  1. There are no such drugs as “anti-depressants”.
    They are “disruptors” as a chemical, and no one has a clue if there are benefits. Some claim so, at the time they claim so. Will they make the same claim a year later?
    Some live on them for years and endure their “depressions” alongside the chemicals.
    Some live on them for years, not having insight that in fact, they have the same ups and downs.
    Some stay on them out of habit.
    Almost always, people eventually catch on that they were never on an “anti-depressant”

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  2. When I was more involved with “mental health” activities, I used to find depressed individuals who experienced numerous perceptual distortions. When treated with B3 and C for the distortions, their moods would improve- misdiagnosing going on that missed proper treatment?

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    • And perhaps it is okay to experience a different reality. Perhaps that reality doesn’t even feel good. Perhaps the battle to be “happy” creates it’s own misery.
      There is a great push not to be “depressed”. Not to be this or that.
      And we have the industry begging us to buy something.
      How about a dose of mindfulness? Or yoga, to “cope”, with adversity, or our “perception” of adversity? I suppose all the oppressed, like slaves and indigenous who felt oppressed and unhappy, should have practiced mindfulness. I mean, some were happy, not all were miserable.
      How about their generations following, which is many of us. Many migrations, much ancestral “stuff” following for generations. It’s part of life, not “mental illness”.

      Memory continues in next generations.

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  3. I agree, “the current approach to treatment resistance is a product of the reductionist medical model, which has been repeatedly challenged in the discipline.” Thanks for reporting on this important topic.

    But I’d like to point out an example of the type of staggering in scope, systemic disrespect that “mental health” clinicians have for their patients, merely by using your own words. You discuss, “illness behavior” and define it as “(patient’s perception, experience, and behavior towards treatment plan).” In other words, you’re claiming the “patient’s perception, experience, and behavior” is “illness behavior,” implying the patient is the illness. Despite the reality that the patient is not an illness, he/she is a person.

    I don’t doubt you speak in these terms because that’s the type language, and attitude towards clients, that all “mental health” workers are taught to speak, and harbor. But this type language, and attitude, is an example of the staggering, and ungodly, disrespect the “mental health” workers have towards their clients. Depersonalizing people by believing their behavior is an “illness behavior” is appalling. People are people, they are not illnesses.

    And it’s kind of sad that you’re a university professor, teaching new “mental health” workers to believe that patients’ behavior is “illness behavior.” A reminder to “treat others in a manner commensurate with how you’d like to be treated” is a lesson that all “mental health” workers need. Would you like to be depersonalized, and called an illness?

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  4. I was reading an article about how a study found people with ADHD have sleep troubles and that explained a large portion of their symptoms. The article mentioned giving them sleep drugs. The article never mentioned that an effect of ADHD drugs is sleep troubles. Instead of blaming the drug it was the patients fault and required more drugs. People who get bipolar from SSRI and stimulants are given more drugs. When you keep giving your patient more deadly drugs to treat side effects of other addicting drug you put them on it begs the question, are you a snake oil salesman? An anatomy of an epidemic answers that question as a yes. These drugs don’t provide any benefits.

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  5. The concept of “treatment resistance” is utterly ridiculous. If I am being paid to fix a car, I don’t get to say the car is “repair resistant” when I can’t figure out how to fix it. It irks the crap out of me that they get away with this kind of nonsense. If they need a label, why not just say, “People who are not helped by our interventions?” Or why not just admit that their whole “treatment regimen” is guesswork and there is no actual expectation that any drug will necessarily be helpful?

    Fava does some really important work. We need more researchers willing to challenge the status quo. But I wish they’d been a little more blunt about calling out the nonsensical and defensive nature of this entire concept.

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    • Admit that they spent their whole life’s work lying to people to get them addicted to deadly drugs that worsen the very symptoms they are supposed to treat? Admit that they made money killing people? That would be refreshing but I’d put my money on denial and cognitive dissonance winning.

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    • Well, a shrink isn’t going to tell you he doesn’t know what’s going on, which is why his supposed treatment failed. Financially and psychologically better for the pro (by his/her own standards) to say you’re treatment resistant than the shrink telling you outright that he doesn’t know enough about your condition to treat it properly, nor does he know anyone who does.

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  6. Treatment resistance related symptoms are all clearly the result of administration side effects and withdrawal side effects after stopping and starting different medications. This sort of outcome is the thesis of Anatomy of an Epidemic, that is, the outcome of drugs over time leaves people an irritable, disabled mess.

    Its amazing that PHARMA gets to cause such suffering with bad or no science, but we are supposed to be so delicate in criticism, supposed to use real science to analyze fake science. The drugs so obviously are the cause of this problem. Why does this need scientific proof? The burden of proof should be on PHARMA to prove that treatment resistance is something other than the effect of drugs.

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    • Hear, hear! It is the responsibility of the researchers to prove their intervention is safe and effective, not the responsibility of detractors to prove them wrong. If there is no proof that “depression,” let alone “treatmeant-resistant depresssion,” actually even exists as an entity, it’s pretty rich to accuse people of being “treatment resistant” just because you don’t know how to help them or are making them worse.

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    • I was thinking about this today. How mind boggling it is, to allow this to go on.

      They do this in real medicine also. I have been shamed for drugs not working.
      In medicine it starts off with “drugs not working”, and leads to innuendos that it’s probably because “patient is depressed”.

      That way, next time one sees a different doc, they play the same game.
      I don’t know how it works in privatized “care”, but for sure public health care, no doctor disagrees with another.

      What I don’t understand is, why does it matter so much to them, that they make crap up?

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      • It shows an incredible degree of defensiveness and insecurity. What’s the big deal about admitting that you don’t know what’s going on and are trying to figure it out? Or that you’re disappointed that the drug didn’t live up to its advertising? If a doctor cares more about patients than ego or income, we wouldn’t see this kind of behavior.

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    • This website had an article about how withdrawal symptoms of SSRI’s and other drugs last almost a year. Psychiatrists will put a patient on a drug and if they don’t improve after a few months they switch drugs and continue doing this. Meaning these people are going through withdrawal from multiple drugs at once. “Treatment resistant” is a euphemism for caused by the “treatment”.

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  7. I agree with much of what you’ve said. However I disagree with your comment on the ineffectiveness of ketamine for ‘treatment resistant depression’. I have been taking it, and it has changed my life for the better, reducing depression and suicidal thinking. I believe drugs are needed for some, and my nutrients (and other pharmaceuticals) were life transforming but not good enough. Once I’ve experienced the iatrogenic and social abuse, and got hooked in the pharmaceutical quagmire, and overused legal and illegal substances like tobacco and cannabis, (which can have medicinal value), and used the either trivial or unacceptable side effects of normal antidepressants….all together led to an impossibly difficult situation. And once again, ketamine has (so far) helped tremendously. I wonder if I can’t get to sleep as early with it, but right now I compromise. I don’t take the insanely expensive nasal form or the inconvenient ‘in office’ form, just a compounded liquid with 15mg of ketamine per dose. And I’m glad every day for it. So please take this in to consideration.

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